2型糖尿病治疗进展 GLP-1受体激动剂 --- 百泌达

内容提要 糖尿病治疗中的困境 肠促胰素效应、肠促胰素及以GLP-1为基础的治疗 艾塞那肽临床注册试验及与胰岛素比较试验 ADA/EASD 治疗方案与艾塞那肽

内容提要 糖尿病治疗中的困境 肠促胰素效应、肠促胰素及以GLP-1为基础的治疗 艾塞那肽临床注册试验及与胰岛素比较试验 ADA/EASD 治疗方案与艾塞那肽

2型糖尿病是一种进行性的疾病: UKPDS 6年的数据 常规治疗 氯磺丙脲 优降糖 胰岛素 二甲双胍 长期保持HbA1c良好控制非常困难 9 8 DISCUSSION Median HbA1c increased over 6 years following randomisation for all treatment groups included in the secondary UKPDS analysis. Patients treated with glibenclamide, metformin, chlorpropamide, or insulin had a decline in HbA1c during the first year following randomisation. BACKGROUND The UKPDS followed 753 subjects with newly diagnosed type 2 diabetes in a randomised controlled trial of conventional therapy (predominantly diet) versus intensive blood-glucose control with metformin (aiming for fasting plasma glucose below 6 mmol/L) over 10 years. A secondary analysis compared 342 subjects allocated metformin with 951 overweight subjects allocated intensive blood-glucose control with chlorpropamide (n=265), glibenclamide (n=277), or insulin (n=409). The median HbA1c during the 10 years of follow-up was 7.4% in the metformin group and 8.0% in the conventional treatment group. The patients assigned intensive control with sulphonylurea or insulin had similar HbA1c to the metformin group. HbA1c (中位数 %) 7 6.2% HbA1c 正常上限 6 1 2 3 4 5 6 随机化以后的时间 (年) UKPDS. Lancet. 1998;352:854-865. Reprinted from Lancet, 352, UKPDS, Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34), 854-865. Copyright 1998, with permission from Elsevier.

2型糖尿病患者  细胞功能随时间而进行性减退 100 80 糖尿病诊断时 细胞功能仅剩50% 60 DISCUSSION Data suggest that the onset of -cell dysfunction may begin years before the development of hyperglycaemia. -cell function may have already declined by 50% at time diabetes is diagnosed. The extent of -cell function remaining is critical because -cell function continues to decline at a rate of approximately ４% per year after diagnosis. BACKGROUND The figure is based on 6-year follow-up from the UKPDS. The rate in decline of -cell function was progressive despite diet, sulphonylurea, or metformin therapy.  细胞功能 (%) 40  细胞功能进行性减退每年约下降 ４% 20 -12 -10 -8 -6 -4 -2 2 4 6 诊断后时间 (年) Holman RR. Diabetes Res Clin Pract. 1998;40(suppl 1):S21-S25.; UKPDS. Diabetes. 1995;44:1249-1258. Reprinted from Diabetes Research and Clinical Practice, 40, Holman RR, Analysis of the United Kingdom Prospective Diabetes Study, S21-S25, Copyright 1998, with permission from Elsevier.

2型糖尿病的药物治疗 影响胰岛素分泌的药物（作用于胰腺） 胰岛素替代 (作用于肝脏、骨骼肌、脂肪) 影响胰岛素效应的药物 胰岛素促泌剂: 磺脲类及格列耐类 胰岛素替代 (作用于肝脏、骨骼肌、脂肪) 胰岛素、预混胰岛素、胰岛素类似物 影响胰岛素效应的药物 抑制肝糖输出 (作用于肝脏) 双胍类 降低胰岛素抵抗 (作用于肝脏、骨骼肌、脂肪) 噻唑烷二酮类和双胍类 延缓碳水化合物的吸收 (作用于肠道) -糖苷酶抑制剂 DISCUSSION Sulphonylureas and meglitinides block the sulphonylurea receptor and ATP-sensitive potassium channels in pancreatic  cells. Their chief adverse events are hypoglycaemia and weight gain. Insulin exerts its effect through the insulin receptor and has hypoglycaemia and weight gain as prominent adverse events. The mode of action of the biguanides (metformin) is not known. Their most significant adverse events are gastrointestinal distress and lactic acidosis. The thiazolidinediones are PPAR-gamma agonists. Their chief adverse events are weight gain, oedema, and anaemia. The -glucosidase inhibitors work in the intestine and have gastrointestinal distress as their most significant adverse event. Moller DE. Nature. 2001;414:821-827.; Pickup JC, Williams G, eds. Textbook of Diabetes 2. Malden, MA: Blackwell;2003:45.5.

内容提要 糖尿病治疗中的困境 肠促胰素效应、肠促胰素及以GLP-1为基础的治疗 艾塞那肽临床注册试验及与胰岛素比较试验 ADA/EASD 治疗方案与艾塞那肽

肠促胰素效应 －口服葡萄糖和静脉注射葡萄糖的效应比较 肠促胰素效应 －口服葡萄糖和静脉注射葡萄糖的效应比较 口服葡萄糖 静脉注射葡萄糖 200 2.0 * 1.5 讨论 肠促胰素效应实际上就是口服葡萄糖和静脉用葡萄糖后胰腺β细胞反应的差别。 口服葡萄糖后的胰岛素反应 (通过C肽测定判断，C肽是胰岛素的替代指标)与静脉用葡萄糖后的胰岛素反应有明显差别。这种差别或效应就是肠促胰素效应，右图的阴影区面积就显示了这种效应。 口服和静脉用葡萄糖后，静脉血浆葡萄糖水平随时间的变化情况差别不大。 背景 这是一项健康人中的交叉研究。 6名年轻的健康志愿者口服25, 50或100g葡萄糖，或者静脉输注相同的葡萄糖。上面图中是用50g葡萄糖后的数据。 C肽可以作为判断胰岛素分泌的指标，比测定血浆胰岛素更好，因为C肽水平不受肝脏提取胰岛素的影响。 口服和静脉用葡萄糖后C太水平的这种差别提示，其他因素 (肠促胰素)也对胰岛素分泌产生了影响，而不仅仅是血糖的直接作用。 肠促胰素效应 100 C肽 (nmol/L) 1.0 静脉血浆葡萄糖 (mg/dL) 0.5 0.0 02 01 02 60 120 180 01 60 120 180 时间 (min) 时间 (min) Mean ± SE; N=6; *p.05; 01-02=glucose infusion time. Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.

2型糖尿病中肠促胰素作用减弱 正常人 2型糖尿病患者 80 80 60 60 胰岛素 (mU/L) 40 40 20 20 30 60 90 静脉注射葡萄糖 口服葡萄糖 正常人 2型糖尿病患者 80 80 讨论 口服葡萄糖后，β细胞分泌胰岛素的情况，可以通过血浆胰岛素升高进行测定，糖尿病患者中口服胰岛素后分泌胰岛素的反应减弱。 静脉输注葡萄糖的180分钟时间内，糖尿病患者表现出的β细胞分泌反应超过对照组受试者，表现在2型糖尿病患者的胰岛素分泌水平比较高。 背景 口服葡萄糖和静脉用葡萄糖后，胰岛素反应的差别是由于除了葡萄糖本身，还存在其他因素的影响，这种影响叫肠促胰素效应；2型糖尿病患者中的肠促胰素效应降低。测定了口服50g葡萄糖后以及等量静脉输注后的胰岛素反应和C肽反应情况。另外，尽量把肠促胰素效应与葡萄糖依赖的促胰岛素多肽 (GIP)反应关联起来。 图中是胰岛素测定的结果。 研究了 14例患者的血浆胰岛素反应情况。 这个研究包括2例糖尿病患者和8名代谢方面健康的对照组受试者。 60 60 胰岛素 (mU/L) 40 40 * * 20 20 30 60 90 120 150 180 30 60 90 120 150 180 时间 (min) 时间 (min) *与口服后的相应值相比p≤.05 Nauck MA, et al. Diabetologia. 1986;29:46-52.

肠促胰素的生理功能 肠促胰素: 肠促胰素产生的促进胰岛素分泌的效应约占餐后胰岛素分泌总量的60％左右 是肠道分泌的激素，可调节胰岛素对摄食的反应 进食后由小肠内分泌细胞分泌 帮助机体在进食碳水化合物后产生适当的餐后胰岛素反应 肠促胰素产生的促进胰岛素分泌的效应约占餐后胰岛素分泌总量的60％左右 讨论 肠促胰素是指在营养成分的作用下，除了营养成分本身的直接作用，还能增强胰岛素分泌的肠道激素。这些激素作用于β细胞，只有在血糖升高的情况下，才增加葡萄糖依赖的胰岛素分泌。 背景 根据C肽水平判断，正常人口服100g葡萄糖后的肠促胰素效应约占餐后总胰岛素释放量的60%。 Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-497; Drucker DJ. Diabetes Care. 2003;26:2929-2940.

两种主要的肠促胰素的比较 GLP-1 GIP 主要合成部位 2型糖尿病患者中分泌 是 否 餐后胰高糖素 食物摄入 延缓胃排空 (回肠和结肠) K 细胞 (十二指肠和空肠) 2型糖尿病患者中分泌 是 否 餐后胰高糖素 食物摄入 延缓胃排空 促进 β 细胞增殖 促进胰岛素生物合成 讨论 这里比较了胰高糖素样肽1 (GLP-1)和葡萄糖依赖的促胰岛素多肽 (GIP) 的特性和生物学作用。 背景 糖尿病患者中的GLP-1分泌减少，由小肠远端和结肠释放。 GLP-1刺激胰岛素分泌，抑制胃排空，抑制胰高糖素分泌，减少进食量，减轻体重，促进β细胞量增多。 糖尿病患者中GIP分泌正常，由十二指肠释放。 GIP刺激胰岛素分泌，对胃排空的作用很小，对胰高糖素分泌没有影响，对饱胀感和体重没有调节作用，可促使β细胞量增多。 Drucker DJ. Diabetes Care. 2003;26:2929-2940. Drucker DJ. Diabetes Care. 2003;26:2929-2940.

2型糖尿病中GLP-1较GIP 具有更强的促进胰岛素分泌的作用 高糖钳夹 GIP GLP-1 (7-36酰胺) 低剂量 GIP 或 GLP-1 (7-36酰胺) 高剂量 GIP 或 GLP-1 (7-36酰胺) 正常人 2型糖尿病患者 讨论 轻度2型糖尿病患者中，胰高糖素样肽1 (GLP-1)仍然保留大部分的促胰岛素活性，这与葡萄糖依赖的促胰岛素多肽(GIP)不同。 GIP和GLP-1都能以剂量依赖的方式增强胰岛素分泌。 输注GLP-1后，2型糖尿病患者中的最大胰岛素作用达到没有糖尿病的受试者中最大胰岛素作用的71% (差别无统计学意义) 输注GIP后，2型糖尿病患者中的最大胰岛素作用比没有糖尿病的受试者中的最大胰岛素作用低54% (p<.05)。 小剂量 GIP (0.8 pmol/kg/min)或GLP-1 (0.4 pmol/kg/min) (7-36酰胺)，大剂量GIP (2.4 pmol/kg/min)或GLP-1 (1.2 pmol/kg/min) 背景 这个图是免疫反应方法测定的高血糖钳夹实验中胰岛素对时间(分钟)作图，包括输注和不输注合成的人GIP或GLP-1。 这张幻灯片的图中的数据来自一个研究，该研究是静脉用合成的人GLP-1和GIP (每组患者n=9)后的促胰岛素效应。 2000 2000 1750 1750 1500 1500 1250 1250 1000 1000 胰岛素 (pmol/L) 750 750 500 500 250 250 30 60 90 120 150 180 210 30 60 90 120 150 180 210 时间 (min) 时间 (min) Mean ± SE; N=18. Nauck MA, et al. J Clin Invest. 1993;91:301-307.

2型糖尿病患者餐后GLP-1水平下降 进餐 20 15 GLP-1 (pmol/L) 10 5 60 120 180 240 正常糖耐量 糖耐量受损 2型糖尿病 进餐 20 * * * * * 讨论 从 60分钟到150分钟的时间内，2型糖尿病患者的餐后胰高糖素样肽1 (GLP-1)浓度比糖耐量正常的人低，差别有统计学意义 (2型糖尿病患者和糖耐量正常的对照组相比p<.05)。 背景 这个研究的主要目的是探讨2型糖尿病患者中肠促胰素效应降低的潜在原因。 研究样本包括54例2型糖尿病患者，15例糖耐量受损的患者，还有33例糖耐量正常的对照组受试者。 这个研究测定了 GLP-1和葡萄糖依赖的促胰岛素多肽(GIP)的分泌情况、测定了脂肪酸、血浆胰岛素浓度、C肽、胰腺多肽和葡萄糖。 这里的图中显示了GLP-1的血浆浓度，用GLP-1的C末端特异性抗体编码方法测定，测定的是GLP-1 (7-36)酰胺及其代谢产物 GLP-1 (9-36)酰胺的总和。 这个研究的结论是：2型糖尿病患者中进餐相关的GLP-1反应降低可能是造成2型糖尿病患者中肠促胰素效应降低的原因。 * 15 * GLP-1 (pmol/L) 10 5 60 120 180 240 时间 (min) Mean ± SE; N=54; * T2DM和NGT组的差别p<.05。 Toft-Nielsen M, et al. J Clin Endocrinol Metab. 2001;86:3717-3723.

GLP-1 在人体中的作用 进食促进 GLP-1分泌 降低β 细胞负荷 增加β 细胞反应 促进饱感 降低食欲 α细胞: 减少餐后胰高糖素分泌 DISCUSSION By decreasing beta-cell workload and improving beta-cell response, the incretin glucagon-like peptide 1 (GLP-1) is an important regulator of glucose homeostasis A thorough understanding of the 5 GLP-1 glucoregulatory effects is important to assess the value of GLP-1 in controlling glucose levels, particularly during the postprandial period Upon ingestion of food, GLP-1 is secreted in into the bloodstream and enhances glucose dependent insulin secretion from beta-cells GLP-1 suppresses inappropriately elevated glucagon secretion from alpha cells Lower levels of glucagon lead to a reduction of glucose output from the liver and indirectly reduce the beta-cell workload By slowing the gastric emptying rate, GLP-1 slows the release of nutrients into the gut allowing more time to control the postprandial increase in glucose levels GLP-1 promotes satiety, potentially through centrally mediated mechanisms BACKGROUND GLP-1 is secreted from L cells of the small intestine GLP-1 decreases beta-cell workload, hence the demand for insulin secretion, by: Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (beta-cell workload) Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on beta-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake Effect on Beta cell: Drucker DJ. Diabetes. 1998;47:159-169. Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand. 1997;160:413-422. Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997;160:413-422. Effects on Stomach: Nauck MA, et al. Diabetologia. 1996;39:1546-1553. Effects on CNS: Flint A, et al. J Clin Invest. 1998;101:515-520. α细胞: 减少餐后胰高糖素分泌 增加β 细胞反应 肝脏: 胰高糖素水平下降 减少肝糖输出 Β细胞: 增强葡萄糖依赖的胰岛素分泌 胃: 帮助调节胃排空 Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.

GLP-1 在2型糖尿病中的作用是 葡萄糖依赖的 安慰剂 GLP-1 安慰剂 安慰剂 安慰剂 GLP-1 GLP-1 GLP-1 270 300 讨论 与安慰剂组相比，连续输注胰高糖素样肽1 (GLP-1)，4小时内血糖水平明显降低。 与安慰剂组相比，GLP-1先是增加胰岛素分泌，但是随着血糖接近正常浓度，尽管继续输注GLP-1，胰岛素的分泌仍然减少，证明这种胰岛素分泌是葡萄糖依赖的。 有高血糖的时候，GLP-1可抑制胰高糖素浓度。但是，随着血糖接近正常水平，尽管继续输注GLP-1，胰高糖素浓度仍然恢复到基线水平，表明在血糖正常和低血糖的情况下GLP-1不抑制胰高糖素。 葡萄糖依赖性的证据是：随着血糖浓度接近正常范围，血浆胰岛素和胰高糖素逐渐恢复到治疗前的浓度。 背景 这个研究包括了2型糖尿病患者(n=10)。所有受试者都进行饮食控制，并服用一种磺脲类(SFU)药物治疗，有些患者用二甲双胍(MET)或阿卡波糖。开始研究的时候停用所有的抗糖尿病药物。 静脉用GLP-1 (7-36酰胺)输注 4小时，速度是 1.2 pmol/kg/min。 20 * 180 200 葡萄糖 (mg/dL) 胰岛素 (pmol/L) 胰高糖素 (pmol/L) * * 10 * * * * * 90 100 * * * * * -30 60 120 180 240 -30 60 120 180 240 -30 60 120 180 240 时间 (min) 时间 (min) 时间 (min) N=10; Mean ± SEM; *p<.05. Nauck MA, et al. Diabetologia. 1993;36:741-744.

GLP-1增强2型糖尿病患者的第一时相胰岛素反应 盐水对照 GLP-1-短时间用药 GLP-1-长期间用药 没有糖尿病的受试者 糖尿病患者* 1800 750 葡萄糖静脉推注 葡萄糖静脉推注 1500 讨论 延长(3小时)胰高糖素样肽 1 (GLP-1)输注时间，在有和无2型糖尿病的患者中都可以增强第一时相的胰岛素反应。 短时间单独用GLP-1，则第一时相的胰岛素释放无明显增多。 背景 这个研究的目的是明确短时间和长时间输注GLP-1对胰岛素反应的影响。 2型糖尿病患者中，第一时相胰岛素释放 (用葡萄糖后的最初10分钟)减少。 这张幻灯片总结了2型糖尿病患者和无糖尿病的对照组受试者中实际测量的 GLP-1对胰岛素释放的影响。 每个受试者进行3次，每次60分钟的静脉葡萄糖耐量试验(IVGTT)，分别在3天的早上进行：1) IVGTT+输注盐水作为对照；2) GLP-1短时间IV输注，在IVGTT之前1-2分钟开始，一直持续到IVGTT结束；3) IVGTT之前3小时开始 GLP-1 IV输注，一直持续到IVGTT 结束。 研究了9例2型糖尿病患者：平均年龄 = 57岁；平均体重指数 (BMI) = 31;平均糖尿病病程 = 8年；HbA1c 范围= 6.7% - 8.5%。9个年龄和体重相匹配的人作为对照。 600 1200 450 胰岛素pmol/L 900 300 600 150 300 -15 15 30 45 60 75 -15 15 30 45 60 75 时间 (min) 时间 (min) Mean ± SE; N=18;长时间输注p<.05;短时间输注p=.33; *注意胰岛素数据的单位刻度不同。 Quddusi S, et al. Diabetes Care. 2003;26:791-798. Reprinted with permission from The American Diabetes Association.

2型糖尿病患者中持续6周皮下输注 GLP-1降低HbA1c 第0周 第6周 HbA1c 8小时血糖谱 12 25 10 9.2% * 讨论 胰高糖素样肽1 (GLP-1)降低了空腹血糖，降低了HbA1c GLP-1组的空腹血糖和餐后血糖都降低，从第1周开始降低，一直持续到6周研究结束。 从第0周到第6周，GLP-1组的 HbA1c也降低了14%，降低幅度有统计学意义(p=.003)。 背景 20例2型糖尿病患者(安慰剂组n=10；GLP-1组 n=10)通过胰岛素泵连续输注6周。 这个研究考察了连续用GLP-1的长期效果。 这个安慰剂对照的概念验证研究表明，2型糖尿病患者连续皮下输注GLP-1，对血糖控制、体重、胰岛素抵抗和β细胞功能都有效果。 基线、第1周和第6周评价的项目包括： HbA1c和果糖胺 β细胞功能(用高血糖钳夹法测定) 膳食耐量试验 (测定8小时血糖、胰岛素、C肽、胰高糖素和游离脂肪酸) 膳食耐量试验 期间评定食欲和副作用 外周组织的胰岛素敏感性 (用正常血糖高胰岛素钳夹法) 结果表明： 在GLP-1组中，空腹血糖和8 h平均血糖分别降低 4.3 mmol/L和5.5 mmol/L (p<.0001) HbA1c 降低了 1.3% (p=.003)，果糖胺降到了正常值 (p=.0002) 空腹游离脂肪酸浓度和8 h平均游离脂肪酸浓度分别降低30%和23% (分别为p=.0005和p= .01) 胃排空受到抑制，体重减轻1.9 kg，食欲减退。 胰岛素敏感性和β细胞功能都得到改善 (分别为p=.003和p=.003）。 未见重要的副作用。 盐水组除了果糖胺浓度升高外，其他指标未见明显变化(p=.0004)。 7.9% 20 8 平均血浆葡萄糖浓度 (mmol/L) 15 平均 HbA1c (%) 6 10 4 5 2 1 2 3 4 5 6 7 8 第 0 周 第 6 周 时间 (hour) Mean ± SE; N=20; 仅显示了用GLP-1治疗的患者的数据； *p=.003. Zander M, et al. Lancet. 2002;359:824-830.

葡萄糖刺激胰岛素分泌的机制 Ca2+ ↑ATP/ADP 胰腺β细胞 葡萄糖 电压依赖性 Ca2+ 通道 K/ATP 通道 讨论 基本的葡萄糖刺激的胰岛素分泌途径包括下列步骤： 葡萄糖通过葡萄糖运输蛋白进入细胞。 葡萄糖代谢引起细胞内三磷酸腺苷 (ATP)升高和细胞内二磷酸腺苷 (ADP)降低，结果是 ATP/ADP比值升高。 ATP/ADP比值升高引起 ATP敏感的钾通道 (K)关闭，引起胞浆膜的去极化。 去极化过程激活电压依赖的钙通道(Ca2+ )，造成Ca2+的内流。 Ca2+的增加刺激胰岛素颗粒的胞吐释放。 背景 一般认为胰高糖素样肽1 (GLP-1)通过调节离子通道的机制（包括ATP敏感的K通道，电压依赖的Ca2+ 通道，电压依赖的K通道和非选择性离子通道）和调节细胞内能量稳态和胞吐作用等机制，增加胰岛素分泌。 ↑ATP/ADP 葡萄糖转运蛋白 胰岛素释放 胰岛素颗粒 GLP-1 受体 胰腺β细胞 Gromada J, et al. Pflugers Arch – Eur J Physiol. 1998;435:583-594; MacDonald PE, et al. Diabetes. 2002;51:S434-S442.

缺乏葡萄糖时激活GLP-1受体 仅引起少量胰岛素释放 电压依赖性 Ca2+通道 K/ATP 通道 讨论 没有葡萄糖的情况下，胰高糖素样肽 1 (GLP-1)信号对胰岛素分泌的作用很小。 GLP-1受体是一种糖蛋白耦合受体，通过环磷酸腺苷 (cAMP)依赖的途径发挥作用，增加细胞内的钙(Ca2+)。 背景 GLP-1对胰岛素分泌的刺激作用是葡萄糖依赖的，需要葡萄糖的浓度正常或升高。 Ca2+ cAMP ATP 胰岛素释放 葡萄糖转运蛋白 胰岛素颗粒 GLP-1受体 胰腺β细胞 Gromada J, et al. Pflugers Arch – Eur J Physiol. 1998;435:583-594; MacDonald PE, et al. Diabetes. 2002;51:S434-S442.

GLP-1的促胰岛素分泌作用 是葡萄糖依赖的 Ca2+ 葡萄糖 电压依赖性 Ca2+ 通道 K/ATP 通道 讨论 胰高糖素样肽1 (GLP-1)的活性和葡萄糖刺激的胰岛素分泌结合起来，共同造成胰岛素分泌增多。 存在 GLP-1激活的途径，则延迟膜的复极化，使钙 (Ca2+)内流的时间延长。 细胞内 Ca2+ 浓度升高使胰岛素释放量进一步增加。 背景 GLP-1对胰岛素分泌的刺激作用是葡萄糖依赖的，需要葡萄糖的浓度正常或升高。 ↑ATP/ADP Ca2+ cAMP ATP 葡萄糖转运蛋白 胰岛素释放 胰岛素颗粒 GLP-1受体 胰腺β细胞 Gromada J, et al. Pflugers Arch – Eur J Physiol. 1998;435:583-594; MacDonald PE, et al. Diabetes. 2002;51:S434-S442.

GLP-1可能影响 细胞功能和细胞量 GLP-1能够： 增加β细胞产生胰岛素的量 (动物和人) 提高β细胞对葡萄糖的反应性 (动物和人) 抑制β细胞减少/增加β细胞再生 (动物) 讨论 胰高糖素样肽 1 (GLP-1)在动物研究和人体内研究中都能提高β细胞分泌胰岛素的量，改善葡萄糖的反应性。 动物研究也表明， GLP-1 可以抑制β细胞减少，促进β细胞再生。 背景 GLP-1 可按剂量依赖的方式增加2型糖尿病患者和对照组患者的胰岛素分泌量。小剂量输注GLP-1后β细胞对葡萄糖的反应性可能恢复到正常水平 。但是， 2型糖尿病患者中，β细胞对葡萄糖的反应性和GLP-1之间的量效关系受到严重破坏1。 新鲜分离的人胰岛中加入GLP-1，可以保留胰岛的形态和功能，抑制细胞凋亡2 GLP-1 刺激胰岛素分泌和生物合成，抑制胰高糖素释放，这两种作用都是葡萄糖依赖的。3 Kjems LL, et al. Diabetes. 2003;52:380-386. Farilla L, et al. Endocrinology. 2003;144:5149-5158. Tourrel C, et al. Diabetes. 2002;51:1443-1452. Kjems LL, et al. Diabetes. 2003;52:380-386; Delmeire D, et al. Biochem Pharmacol. 2004;68:33-39; Farilla L, et al. Endocrinology. 2003;144:5149-5158; Tourrel C, et al. Diabetes. 2002;51:1443-1452.

GLP-1组中，胰岛素敏感性升高77% (p=.002) 第0周 2型糖尿病患者 第6周 p=.006 GLP-1组中，胰岛素敏感性升高77% (p=.002) 700 600 讨论 这个研究表明，根据C肽的测定结果，6周时间内胰高糖素样肽 1 (GLP-1)改善了2型糖尿病患者的β细胞功能。 GLP-1治疗的患者，第6周时C肽结果稳定可靠。 安慰剂组6周后的C肽浓度变化不大。 背景 这个研究考察了连续用GLP-1的长期效果。 20例2型糖尿病患者(安慰剂组n=10；GLP-1组 n=10)通过胰岛素泵连续输注6周。 这个安慰剂对照的概念验证研究表明，2型糖尿病患者连续皮下输注GLP-1，对血糖控制、体重、胰岛素抵抗和β细胞功能都有效果。 基线、第1周和第6周评价的项目包括： HbA1c和果糖胺 β细胞功能(用高血糖钳夹法测定) 膳食耐量试验 (测定8小时血糖、胰岛素、C肽、胰高糖素和游离脂肪酸) 膳食耐量试验 期间评定食欲和副作用 外周组织的胰岛素敏感性 (用正常血糖高胰岛素钳夹法) 对C肽进行免疫测定，评价2型糖尿病患者中胰腺的β细胞分泌功能。 500 400 C-肽 (pmol/L) 300 200 100 GLP-1组 盐水组 Mean ± SE; N=19; 变化值的组间差别 p=.02. Zander M, et al. Lancet. 2002;359:824-830.

大鼠糖尿病模型中GLP-1 激活 β 细胞新生 7天龄大鼠的胰岛素免疫组化 未经处理的糖尿病大鼠 用GLP-1治疗的糖尿病大鼠 讨论 第7天，开始治疗后5天，胰高糖素样肽1 (GLP-1)治疗，通过刺激β细胞新生和再生，增加了胰腺中胰岛素的含量以及β细胞的总量。 背景 出生后第1周的第2-6天，给Goto-Kakizaki (GK) 大鼠注射GLP-1 (400 μg/kg duct (d)) 或者exendin-4 (3 μg/kg d; 未给出)。生后第7天和2个月的时候，分别评价β细胞的量和胰腺功能。 图中所示为注射GLP-1后得到的结果。 GK大鼠是2型糖尿病的遗传模型，最早在出生后3周可以检测到动物的基础高血糖。 大鼠胰腺的组织切片通过过氧化物酶间接标记技术对胰岛素进行免疫染色。 从第7天随访到成年(2个月)，结果表明 GLP-1治疗对β细胞量有长期的有利影响。 7天龄大鼠的胰岛素免疫组化 Tourrel C, et al. Diabetes. 2002;51:1443-1452.

体外试验中GLP-1 减少  细胞凋亡 * 200 150 和第一天测定的值相比的％ 细胞内 bcl-2 水平 100 50 1 3 5 对照 200 GLP-1 GLP-1 150 讨论 胰高糖素样肽 1 (GLP-1)除了对胰岛特异性基因的表达及胰岛细胞的量有作用外，还具有抗细胞凋亡的作用。 这个研究的目的是探讨 GLP-1保留新鲜分离的人胰岛的活力及其功能的能力。 研究发现有证据说明，新鲜分离的人胰岛中加入GLP-1，可以保留胰岛的形态和功能，抑制细胞凋亡。 背景 新鲜分离的人胰岛中加入GLP-1，可以保留胰岛的形态和功能，抑制细胞凋亡。 在有或无GLP-1 (10nM, 每 12 h加1次)的条件下，对人胰岛培养 5天，研究胰岛的活力，检测促凋亡因子 (capspase-3)和抗凋亡因子 (bcl-2)的表达情况，以及葡萄糖依赖的胰岛素产生量。 他们发现 GLP-1处理过的胰岛中，胰岛的三维形态保存得比对照组好。核浓缩是细胞凋亡的特征之一，加入GLP-1可抑制细胞核浓缩。GLP-1处理过的胰岛中，凋亡细胞的数量减少，这种现象在第3天最为明显。 人胰岛中加入 GLP-1，可显著上调抗凋亡分子bcl-2的表达 (与对照相比p<.01) 上面的图显示了对照组和 GLP-1处理的胰岛中 Bcl-2的表达情况。用胰岛免疫染色方法，进行至少5次，通过分析荧光染料分子FITC (bcl-2)和罗丹明(capspase-3)所释放的信号的方差，将抗凋亡和促凋亡的细胞蛋白成分的定量测定结果外推。 Farilla L, et al. Endocrinology. 2003;144:5149-5158. 和第一天测定的值相比的％ 细胞内 bcl-2 水平 100 * 50 1 3 5 时间 (天) 与对照组相比，培养的人胰岛细胞中加入 GLP-1后，抗凋亡分子bcl-2的表达明显上调(*与对照组相比p<.01) Farilla L, et al. Endocrinology. 2003;144:5149-5158.

在体内DPP-4快速降解 GLP-1限制其作用时间 50 nmol 5 nmol 0.5 nmol 100000 10000 1000 Log Mean (SE) 血浆GLP-1 (pM) 讨论 胰高糖素样肽 1 (GLP-1)迅速被二肽基肽酶-4 (DPP-4)灭活，这样就限制了其对糖尿病的治疗作用。 啮齿类动物中，皮下注射GLP-1后，GLP-1的血浆浓度迅速降低。 背景 这个研究比较了 GLP-1 (皮下注射)在雄性Sprague-Dawley大鼠(n=4-7)中的药代动力学特点（p<.05） GLP-1-(7-36)-酰胺以4个不同的剂量注射：0.05, 0.5, 5和50 nmol (未显示0.05 nmol的数据) GLP-1的半衰期从4.7 ± 0.8分钟(min)到7.1 ± 2.4 min。 100 10 1 -1 1 2 3 4 5 6 一次性皮下注射后时间 (hour) 二肽基肽酶-4 (DPP-4) 降解 GLP-1 H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R – NH2 GLP-1 人 Mean ± SEM;N=4-7 (大鼠); p<.05. Adapted from Parkes D, et al. Drug Dev Res. 2001;53:260-267; Eng J, et al. J Biol Chem. 1992;267:7402-7405.

GLP-1小结 2型糖尿病患者中GLP-1分泌减少 GLP-1 作用于全身多个靶点降低血糖 GLP-1 被二肽基肽酶- (DPP-4) 快速降解

快速灭活限制了GLP-1 的临床治疗价值 快速灭活 (DPP-4), 清除半衰期短 (~1-2 min) DISCUSSION Despite its favourable biological actions, the therapeutic potential of glucagon-like peptide 1 (GLP-1) is limited primarily by its rapid degradation by the ubiquitous enzyme dipeptidyl peptidase-4 (DPP-4) The rapid inactivation of GLP-1, in addition to its rapid renal clearance, contributes to a short half-life of less than two minutes. Thus, sustaining plasma concentrations of GLP-1 long enough to produce a therapeutic effect requires continuous administration. As is typical of other peptides, GLP-1 requires administration by injection BACKGROUND Although single or repeated subcutaneous injections of native GLP-1 decrease blood glucose in human subjects, the glucose-lowering effects are transient and no longer evident 1–2 h after peptide injection Furthermore, continuous enhancement of GLP-1 action for 24 h/day appears superior for glucose control compared with peptide infusion for 16 h. Continuous intravenous or subcutaneous infusion of GLP-1 in short- and long-term studies has been shown to be highly effective in lowering blood glucose in diabetic subjects, but this intensive and expensive approach has major limitations for the treatment of large numbers of diabetic patients. The rapid degradation and clearance of native endogenous and exogenously administered GLP-1 spurred the clinical development of degradation-resistant GLP-1 analogs with longer durations of action in vivo GLP-1 必须持续给药 (静脉注射) 用于治疗2型糖尿病这样的慢性疾病非常不便 Drucker DJ, et al. Diabetes Care. 2003;26:2929-2940.

目前以GLP-1为主改善血糖控制的方法 模拟 GLP-1作用的药物 延长内源性GLP-1活性的药物 不被DPP-4降解的GLP-1衍生物 艾塞那肽 延长内源性GLP-1活性的药物 DPP-4抑制剂 讨论 根据胰高糖素样肽1 (GLP-1)的治疗作用，已经开发出了一些药物： 肠促胰素类似物 – 艾塞那肽是这类药物中的第一个产品，可用于治疗2型糖尿病 蛋白酶二肽基肽酶 (DPP)-4的抑制剂 –例如，西他列汀（sitagliptin）和维格列汀（vildagliptin）都是 DPP-4抑制剂。 背景 肠促胰素类似物通过模拟 GLP-1而发挥作用，而DPP-4抑制剂通过抑制 DPP-4可延长内源性GLP-1的活性持续时间， DPP-4 是灭活肠促胰素的主要的酶。 Drucker DJ, et al. Diabetes Care. 2003;26:2929-2940

艾塞那肽: 一种肠促胰岛素分泌激素拟似物 体外试验中与人 细胞表面GLP-1受体结合 能抵抗DPP-4降解灭活作用 艾塞那肽 (Exendin-4) 人工合成的赫拉毒蜥唾液中的一种蛋白质 与人GLP-1约有50％的同源性 体外试验中与人 细胞表面GLP-1受体结合 能抵抗DPP-4降解灭活作用 DISCUSSION Exenatide (exendin-4) is the synthetic version of salivary protein found in the Gila monster Position 2 of the amino acid sequence is different between glucagon-like peptide 1 (GLP-1) and exenatide, making exenatide resistant to dipeptidyl peptidase-4 (DPP-4) enzymatic degradation BACKGROUND Exendin-4 is a naturally occurring incretin hormone in the Gila monster Heloderma suspectum Gila monsters produce exendin-4, which is a separate and distinct protein compared to human GLP-1 Exendin-4 mimics some of the actions of GLP-1 in vivo Exendin-4 exerts some of its antidiabetic actions via unknown mechanisms 艾塞那肽 H G E G T F T S D L S K Q M E E E A V R L F I E W L K N G G P S S G A P P P S – NH2 人GLP-1 H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R – NH2 DPP-4灭活位点 Adapted from Nielsen LL, et al. Regulatory Peptides. 2004;117:77-88. Reprinted from Regulatory Peptides, 117, Nielsen LL, et al, Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycaemic control of type 2 diabetes, 77-88, 2004, with permission from Elsevier for English use only.

艾塞那肽 (Exendin-4)在循环中滞留的时间长于GLP-1 50 nmol 5 nmol 0.5 nmol Exendin-4 GLP-1 100000 100000 DISCUSSION This study shows that exendin-4 exhibits significantly longer plasma half-life than active glucagon-like peptide 1 (GLP-1) in rats In rats, after subcutaneous administration of GLP-1, plasma concentrations of GLP-1 declined quickly BACKGROUND This study compared the pharmacokinetics of GLP-1 vs exendin-4 (injected subcutaneously) in male Sprague-Dawley rats GLP-1-(7-36)-amide was injected at four different doses: 0.05, 0.5, 5, and 50 nmol (0.05 nmol data not shown) GLP-1 half-life values ranged from 4.7 ± 0.8 minutes (min) to 7.1 ± 2.4 min Exendin-4 half-life values ranged from 90 ± 3 min to 216 ± 13 min Its longer plasma half-life may render exendin-4 an attractive prospect for the treatment of diabetes 10000 10000 1000 1000 Log Mean (SE) Plasma Exendin-4 (pM) Log Mean (SE) Plasma GLP-1 (pM) 100 100 10 10 10 10 1 2 3 4 5 6 1 2 3 4 5 6 一次性皮下注射后的时间 (小时) 一次性皮下注射后的时间 (小时) N = 4-7 (rats); p<.05. Adapted from Parkes D, et al. Drug Dev Res. 2001;53:260-267. Reprinted with permission from John Wiley & Sons, Inc.

艾塞那肽 （Exendin-4） 每日一次治疗2周后增加糖尿病小鼠胰岛体积 DISCUSSION The photomicrographs shown here demonstrate increased pancreatic islet size in diabetic mice treated with exendin-4 Islet size increased by a factor of approximately 1.8 after 2 weeks of daily exendin-4 treatment versus treatment with saline BACKGROUND This study was performed to determine whether GLP-1 (data not shown) and exendin-4 could enhance pancreatic expression of transcription factors critical to -cell neogenesis and pancreas development Diabetic (db/db) mice were given saline or an exendin-4 intraperitoneal injection (100 pmol/kg) daily for 2 weeks The mice fasted overnight, euthanized by carbon dioxide asphyxiation, and the pancreases were dissected. The islet cells were visualised via immunofluorescence staining. 1 2 3 胰岛面积 (Arbitrary Units X 104) 生理盐水 Exendin-4 生理盐水 Exendin-4 Mean (SE). Stoffers D, et al. Diabetes. 2000;49:741-748. Copyright © 2000 American Diabetes Association. From Diabetes, Vol 49, 2000; 741-748. Reprinted with permission from The American Diabetes Association.

艾塞那肽是一种新的肠促胰素类似物，其血糖调节机制与人GLP-1相似 增强葡萄糖依赖的胰岛素分泌 减少餐后胰高糖素分泌 延缓胃排空 减少食物摄入，减轻体重 恢复1相胰岛素分泌 增加  细胞量 ( 动物模型)，改善  细胞功能 DISCUSSION Summarise all points

内容提要 糖尿病治疗中的困境 肠促胰素效应、肠促胰素及以GLP-1为基础的治疗 艾塞那肽临床注册试验及与胰岛素比较试验 ADA/EASD 治疗方案与艾塞那肽

艾塞那肽的主要临床试验 2993-112 (30周)：艾塞那肽＋二甲双胍 2993-113 (30周)：艾塞那肽＋磺脲类 AMIGO* 2993-115 (30周)：艾塞那肽＋二甲双胍＋磺脲类 2993-112E (52周) 2993-113E (52周) 2993-117 2993-119 (2年、3年) 2993-115E (52周) （开放标签延伸试验） GWAA：艾塞那肽 vs 甘精胰岛素（与二甲双胍及磺脲类合用）[平行试验] GWAO：艾塞那肽 vs 甘精胰岛素（与二甲双胍或磺脲类合用）[交叉试验] GWAD：艾塞那肽 vs 预混门冬胰岛素（与二甲双胍及磺脲类合用） 艾塞那 vs 西他列汀作用机制研究 GWBA：亚洲人艾塞那肽＋二甲双胍＋磺脲类 *AMIGO: AC2993 Diabetes Management for Improving Glucose Outcomes

安慰剂 5 µg (0.02 mL) or 10 µg (0.04 mL) BID 大型3期临床试验：试验设计 2型糖尿病患者中进行的随机、双盲、安慰剂对照、多中心研究 无清洗期 早餐及晚餐前皮下注射艾塞那肽或安慰剂 DISCUSSION Three AMIGO trials were conducted to evaluate exenatide treatment in patients with type 2 diabetes Patients were randomised to 1 of 4 treatment regimens following a 4-week lead-in period with 0.02 mL placebo injection BACKGROUND Patients were instructed to continue taking their oral diabetes medications, with exenatide added as adjunct therapy to the existing drug regimens Exenatide was self-administered by patients as subcutaneous twice daily (BID) 15 minutes before the morning and evening meals Both exenatide regimens began with 5 µg exenatide for 4 weeks to minimise nausea, and placebo groups were combined for analyses Participants could terminate the study under the following conditions: HbA1c up 1.5% from baseline or HbA1c >11.5% at week 18 or 24 or Fasting glucose >240 mg/dL (lab test), or Fasting glucose >260 mg/dL (finger stick) for 2+ weeks 艾塞那肽 5 µg (0.02 mL) BID 艾塞那肽 5 µg (0.02 mL) BID 安慰剂 导入 0.02 mL BID 艾塞那肽 10 µg (0.04 mL) BID 筛查 Placebo0.02 mL BID 安慰剂 5 µg (0.02 mL) or 10 µg (0.04 mL) BID -4 4 12 24 30 时间 (周) DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.; Buse JB, et al. Diabetes Care. 2004;27:2628-2635.; Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.

大型3期临床试验：合并结果 艾塞那肽降低 HbA1c 及体重 安慰剂 BID 艾塞那肽 5 µg BID 艾塞那肽 10 µg BID -0.5 -1.5 -1 -0.9 * -0.6 +0.1 -0.7 -1.4 * -1.9 -2.0 -1.5 -1.0 -0.5 DISCUSSION Combined results from all 3 AMIGO studies demonstrated that exenatide significantly improved glycaemic control based on reduced HbA1c levels, and significantly reduced body weight regardless of treatment regimen (5 µg or increase to 10 µg) BACKGROUND The 3 AMIGO studies were undertaken to evaluate the ability of exenatide to improve glycaemic control in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of metformin (MET), sulphonylurea (SFU), or MET + SFU Three 30-week, placebo-controlled, double-blind, Phase 3 studies were completed in the United States This slide presents combined data Subjects with type 2 diabetes (currently taking MET, SFU, or MET + SFU) were randomised to Placebo (PBO), n = 483; 5 µg exenatide BID, n = 480; or 10 µg exenatide twice daily (BID), n = 483; N = 1446. All subjects also continued current medication. Baseline HbA1c: placebo, 8.5%; 5 μg exenatide BID, 8.4%; 10 μg exenatide BID, 8.5% Baseline weight: placebo, 99 kgs (218 lbs); 5 μg exenatide BID, 97 kgs (213 lbs); 10 μg exenatide BID, 98 kgs (216 lbs) The Last Observation Carried Forward (LOCF) method was applied to the data Weight change was a secondary endpoint 体重变化 (kg) HbA1c变化(%) ITT 30-week data; N = 1446; Mean (SE); *p<0.005; Weight was a secondary endpoint. Data on file, Amylin Pharmaceuticals, Inc.

大型3期临床试验： 30周时艾塞那肽降低餐后血糖 安慰剂 BID 艾塞那肽 5 µg BID 艾塞那肽 10 µg BID 多个3期临床试验的合并结果 基线 30周 5 -30 30 60 90 120 150 180 16 6 7 8 9 10 11 12 13 14 15 安慰剂 -30 30 60 90 120 150 180 5 8 11 13 16 15 14 12 10 9 7 6 艾塞那肽 DISCUSSION Combined results from all 3 AMIGO studies at Week 30 demonstrated a significant reduction (p<.0001) in postprandial glucose (PPG) versus Day 1 for all patients treated with exenatide, regardless of treatment regimen (5 µg or increase to 10 µg) BACKGROUND The 3 pivotal studies were undertaken to evaluate the ability of exenatide to improve glycaemic control in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of metformin (MET), sulphonylurea (SFU), or MET + SFU Three 30-week, placebo-controlled, double-blind, Phase 3 studies were completed in the United States This slide presents combined data Subjects with type 2 diabetes (currently taking MET, SFU, or MET + SFU) were randomised to placebo (PBO), 5 µg exenatide BID, or 10 µg exenatide twice daily (BID), N = 1446. All subjects also continued current medication. The Last Observation Carried Forward (LOCF) method was applied to the data A subgroup of subjects in each treatment regimen underwent meal tolerance tests at baseline, Week 4, and Week 30. Data from baseline and week 30 are shown here. Meal size was calculated individually at baseline to provide 20% of total daily calories (macronutrient composition: 55% carbohydrate/15% protein/30% fat), with the standard breakfast given 15 minutes after exenatide injection The Evaluable Meal Tolerance Cohort had the following treatment breakdown: MET (n = 36); SFU (n = 25); MET + SFU (n = 77) 5 µg exenatide BID subgroup (n = 42); 10 µg exenatide BID subgroup (n = 52); placebo subgroup (n = 44) 进餐 进餐 血糖 (mmol/L) 时间 (min) 时间 (min) Mean (SE); N = 138; Evaluable meal tolerance cohort. p<.0001 for change in PPG from baseline to week 30, exenatide vs placebo group. Data on file, Amylin Pharmaceuticals, Inc.

大型3期临床试验：合并结果 常见不良事件 30周艾塞那肽3期试验合并结果 安慰剂 (N = 483) 5 µg艾塞那肽 (N = 480) 大型3期临床试验：合并结果 常见不良事件 30周艾塞那肽3期试验合并结果 安慰剂 (N = 483) 5 µg艾塞那肽 (N = 480) 10 µg 艾塞那肽 (N = 483) DISCUSSION In assessing combined results from all 3 AMIGO studies, the most common adverse events were nausea and hypoglycaemia BACKGROUND Three 30-week, double-blind, Phase 3 studies have been completed in the United States: Patients with type 2 diabetes randomised to placebo, 5 µg exenatide twice daily (BID), or 10 µg exenatide BID with metformin (MET), Intent to Treat (ITT) N = 336 Patients with type 2 diabetes randomised to placebo, 5 µg exenatide BID, or 10 µg exenatide BID with a sulphonylurea (SFU), ITT N = 377 Patients with type 2 diabetes randomised to placebo, 5 µg exenatide BID, or 10 µg exenatide BID with MET and SFU, ITT N = 733 In general, nausea was mild-to-moderate and had a minimal to moderate effect on daily activities. The incidence of nausea decreased over time. Likewise, hypoglycaemia was mostly mild-to-moderate in intensity. One severe hypoglycaemic event occurred in a patient receiving SFU (within the 5 µg exenatide treatment regimen). Exenatide did not increase the incidence of hypoglycaemia when combined with MET. Mild-to-moderate hypoglycaemia incidence increased in groups where exenatide was added to a SFU. Hypoglycaemia was defined as follows: Mild-to-moderate hypoglycaemia: subject reported symptoms consistent with hypoglycaemia that may have been documented by a plasma glucose concentration value (<3.33 mmol/L) Severe hypoglycaemia: subject required the assistance of another person to obtain treatment for their hypoglycaemia; treatment included oral carbohydrate, intravenous glucose, or intramuscular glucagon 48% 39% 18% 恶心 25% 15% 8% 低血糖 15% 11% 6% 腹泻 13% 4% 呕吐 7% 10% 6% 头痛 10% 9% 4% 抖动感 Data on file, Amylin Pharmaceuticals, Inc.

大型3期临床试验（合并结果）： 恶心随时间延长而减少 大型3期临床试验（合并结果）： 恶心随时间延长而减少 100 安慰剂 5 µg 艾塞那肽 BID 10 µg 艾塞那肽 BID 75 60 第4周时剂量从5 µg 增加至10 µg 的患者 恶心发生率 (%) 45 30 CITATION Data on file, Amylin Pharmaceuticals, Inc. DISCUSSION In assessing combined results from all 3 AMIGO studies, incidence of nausea, shown in 4-week intervals, generally decreased over time for all treatment regimens BACKGROUND The 3 AMIGO studies were undertaken to evaluate the ability of exenatide to improve glycaemic control in patients with T2D failing to achieve glycaemic control with maximally effective doses of MET, SFU, or MET + SFU Three 30-week, placebo-controlled, double-blind, Phase 3 studies were completed in the United States This slide presents combined data Subjects with T2D (currently taking MET, SFU, or MET + SFU) were randomised to placebo, 5-µg exenatide BID, or 10-µg exenatide BID, N=1446. All subjects also continued current medication The last observation carried forward (LOCF) method was applied to the data Because the incidence of nausea did not rise significantly at the 10-µg dose, it suggests that titration from a lower dose of exenatide minimised any increase in nausea 15 0-4 >4-8 >8-12 >12-16 >16-20 >20-24 >24-28 >28 时间 (周) ITT 30-week data; N=1446. Data on file, Amylin Pharmaceuticals, Inc.

艾塞那肽治疗3年HbA1c 及体重的改变 基线 8.2 ± 0.1% 基线 99.3 ± 1.2 kg 10 156 周 基线 8.2 ± 0.1% 基线 99.3 ± 1.2 kg 10 156 周 -1.0% (95% CI: -1.1 to -0.8%; p<0.0001) 156 周 -5.3 kg (95% CI: -6.0 to -4.5 kg; p<0.0001) 9 8 (%) -2 CITATION Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24:275-286. SEE pg 279 Figure 2-A,D (for slide data); pg 278 2nd column 1st and 3rd paragraph (for DISCUSSION) DISCUSSION At Week 156, patients completing 3 years of exenatide treatment (n=217) had reduced HbA1c (-1.0 ± 0.1%; 95% confidence interval [CI]: ‑1.1 to ‑0.8%; p.0001), fasting plasma glucose (FPG) (‑1.30 ± 0.21 mmol/L; 95% CI: ‑1.73 to ‑0.89 mmol/L; p.0001), body weight (-5.3 ± 0.4 kg; 95% CI: ‑6.0 to ‑4.5 kg; p.0001) The reductions in HbA1c and FPG were evident as early as Week 12 (‑1.1 ± 0.1% and ‑1.27 ± 0.15 mmol/L, respectively), indicating a sustained glycaemic effect 46% of patients achieved HbA1c of ≤7%; 30% achieved HbA1c ≤6.5% Similar trends were observed for a more conservative analysis using the intent-to-treat (ITT) population. Changes from baseline to Week 156 in the ITT population were HbA1c: ‑0.6 ± 0.1%, FPG: ‑0.78 ± 0.14 mmol/L, and weight: ‑3.9 ± 0.2 kg. HbA1c reductions were similar across different baseline body mass index (BMI) stratifications: ‑0.9 ± 0.2% for baseline BMI 30 kg/m2 (n=63) and ‑1.0 ± 0.1% for baseline BMI 30 kg/m2 (n=154) In the 170 patients with baseline HbA1c 9% (mean 7.8%), HbA1c change was ‑0.6 ± 0.1%. In the 47 patients with baseline HbA1c 9% (mean 9.7%), HbA1c change was ‑2.1 ± 0.2%. Alanine aminotransferase (ALT) declined progressively (p.0001 versus baseline). No change in aspartate aminotransferase (AST) (p=.2029). Weight change was mildly correlated with baseline ALT (r=‑.01) or ALT change (r=.31) The correlation between HbA1c change and ALT change (r=.25) was also low In a subgroup of the 3-year completer population in whom data were collected for analyses (N=92), baseline HOMA‑B was 52.4 ± 3.9%. Exenatide treatment was associated with sustained HOMA-B improvement over time (70.1 ± 4.4%; p.0001 versus baseline). No consistent change was observed in HOMA-S. SLIDE BACKGROUND Patients with type 2 diabetes mellitus treated with metformin (MET) and/or sulphonylurea (SFU) were randomised to receive placebo or exenatide in the original placebo-controlled, double-blind, Phase 3, randomised trials and received exenatide in the subsequent open-label extensions At the time of this analysis, all patients (N=217) had received 3 years of exposure to exenatide A subgroup of 151 patients completed 3.5 years of exenatide and also had serum lipid measurements available for analysis ALT and AST are hepatic biomarkers 1c 7 Weight Change from Baseline (kg) HbA 6 -4 5 4 -6 26 52 78 104 130 156 26 52 78 104 130 156 治疗 (周) 治疗 (周) N=217; Mean Adapted from Klonoff DC, et al. Curr Med Res Opin 2008;24:275-286.

基线 HbA1c 9% 的患者艾塞那肽治疗后HbA1c变化情况 开放标签延伸期研究 基线 HbA1c (%) 基线 HbA1c 9% (n=59) 9.7 基线 HbA1c <9% (n=182) 7.8 30周 130周 0.0 -0.5 -0.7% Change in HbA1c (%) -1.0 -0.9% -1.5 DISCUSSION POINTS Patients with baseline HbA1c ≥9% had greater mean HbA1c reductions with exenatide treatment than did patients with baseline HbA1c <9% SLIDE BACKGROUND Shown are 30- and 130-week data for 241 patients, combined from Cohorts 1 and 2, who had received 2.5 years of exposure to exenatide Cohort 1: Patients who received exenatide (not placebo) in the 30-week, placebo-controlled trials continued exenatide treatment throughout participation in the open-label extension trials and subsequent long-term maintenance trial Therefore, Cohort 1 completed 130 weeks of exenatide exposure at study Week 130 Cohort 2: Patients who received placebo in the placebo-controlled trials then received exenatide treatment from Week 30, the start of the open-label extension trials, and continued in the subsequent long-term maintenance trial Therefore, Cohort 2 completed 130 weeks of exenatide exposure at study Week 160 See accompanying Prescribing Information and safety information included in this presentation REFERENCE Data on file, Amylin Pharmaceuticals, Inc. -2.0 -2.0% -2.1% -2.5 2.5-year completers; n=241 at weeks 30 and 130; mean ± SE Data on file, Amylin Pharmaceuticals, Inc. 41

安慰剂对照开放延伸试验(合并): 3.5年时脂代谢改变 安慰剂对照研究/开放标签延伸期研究 (合并) 平均变化 (%) N=151; *p<.001 **p<.05 TG LDL TC * +24% -5% -6% -12% -20 -15 -10 -5 5 10 15 20 25 30 SBP DBP - 4% -2% HDL ** CITATION Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24:275-286. SEE pg 275 2nd column 1st paragraph and pg 280 1st column 2nd paragraph (for slide data and DISCUSSION) DISCUSSION In a subset of exenatide-treated patients who completed 3.5 years of treatment, improvements in triglycerides, LDL-C, TC, and HDL-C were noted Mean percentage changes from baseline were: triglycerides -12%, LDL-C -6%, TC -5%, and HDL-C 24% Although 25% of subjects who lost the most weight had the greatest improvements in triglycerides and HDL-C, overall there was a minimal correlation between weight change and serum lipid change BACKGROUND Patients with T2D treated with MET and/or SFU were randomised to receive placebo or exenatide in the original placebo-controlled, double-blind, Phase 3, randomised trials and received exenatide in the subsequent open-label extensions At the time of this analysis, all patients (N=151) had received 3.5 years of exposure to exenatide TG = triglycerides; SBP = systolic BP; DBP = diastolic BP Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.

开放延伸试验小结 在用二甲双胍和/或磺脲类药物治疗的2型糖尿病患者中加用艾塞那肽治疗≥3 年： 显著持续改善血糖控制 进行性降低体重 改善血脂及血压 年龄 ≥65 岁的患者中效果相同 恶心及其它胃肠道副反应以及低血糖一般为轻度到中度 正在研究艾塞那肽可能给糖尿病患者带来的其它好处 CITATION Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24:275-286. SEE pg 285 “Conclusion” and 1st column 2nd paragraph (for slide data and DISCUSSION) DISCUSSION Three or 3.5 years of exenatide treatment was associated with improvements in HbA1c, body weight, and cardiovascular risk markers SLIDE BACKGROUND Patients with type 2 diabetes mellitus treated with metformin (MET) and/or sulphonylurea (SFU) were randomised to receive placebo or exenatide in the original placebo-controlled, double-blind, Phase 3, randomised trials and received exenatide in the subsequent open-label extensions At the time of this analysis, all patients (N=217) had received 3 years of exposure to exenatide A subgroup of 151 patients completed 3.5 years of exenatide and also had serum lipid measurements available for analysis Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.

交叉设计的艾塞那肽和甘精胰岛素对照试验 随机 交叉 筛查 治疗阶段 I 治疗阶段 II 艾塞那肽 10 mg (BID)† CITATION Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333-2348. SEE pg 2335 “Study design” (for slide data and DISCUSSION); pg 2346 “Clinical therapeutics” (for DISCUSSION) DISCUSSION This multicentre (26 sites), open-label, randomised, 2-period crossover noninferiority study assessed the efficacy and safety of exenatide and insulin glargine treatments in patients with type 2 diabetes treated with either metformin (MET) or a sulphonylurea (SFU) Within 2 weeks of screening, eligible patients were randomly assigned, within screening HbA1c stratum (<8.5% or ≥8.5%) and with equal probability, to treatment with exenatide followed by glargine (16 weeks each) or the reverse sequence. STUDY H8O-MC-GWAO BACKGROUND Randomised, open-label, 2-period crossover noninferiority study of patients with type 2 diabetes previously uncontrolled with MET or an SFU. Exenatide and insulin glargine treatments were administered for 16 weeks each and prestudy dose of MET or SFU was continued. Exenatide was administered twice daily as subcutaneous injection, 60 min before AM and PM meals at 5 µg for first 4 weeks, 10 µg exenatide after 4 weeks. Once-daily insulin glargine treatment was initiated at 10 IU, and was increased weekly by 8, 6, 4, or 2 IU daily if the mean fasting serum glucose (FSG) level on two consecutive days was >10 mmol/L, 7.8 to 10 mmol/L, 6.7 to 7.8 mmol/L, or 5.6 to 6.7 mmol/L, respectively. However, if the mean FSG level was less than 4 mmol/L at any time during the previous week, the insulin glargine dose was not adjusted. 患者: MET 或 SFU HbA1c ≥7.1% 及 ≤11.0% MET or SFU SFU 或 MET SFU or MET 甘精胰岛素 (QD)‡ 甘精胰岛素 (QD)‡ 治疗周数 ± 1 -2 16 32 †Patients were treated with 5 µg exenatide BID for the first 4 weeks and then 10 µg exenatide BID thereafter; ‡Insulin glargine was titrated targeting a fasting glucose ≤5.6 mmol/L. Mean endpoint insulin glargine dose: Treatment Period 1, 28.6 ± 16.8 IU/day (n=69); Treatment Period 2, 25.7 ± 17.6 IU/day (n=57). Barnett AH, et al. Clin Ther. 2007;29:2333-2348.

艾塞那肽/甘精胰岛素对比试验: 患者基线特征 (n=68) 甘精胰岛素/ 艾塞那肽 (n=70) 总数 (N=138) HbA1c (%) 8.89 ± 0.13 9.00 ± 0.13 8.95 ± 0.09 空腹血糖 (mmol/L) 11.8 ± 0.4 12.2 ± 0.4 12.0 ± 0.3 糖尿病病程 (年) 6.6 ± 0.6 8.3 ± 0.7 7.4 ± 0.4 年龄 (岁) 54.5 ± 1.1 55.3 ± 1.2 54.9 ± 0.8 性别, 男性 (%) 48.5 45.7 47.1 体重 (kg) 85.6 ± 2.0 84.0 ± 2.0 84.8 ± 1.4 BMI (kg/m2) 31.3 ± 0.5 30.9 ± 0.5 31.1 ± 0.4 口服降糖药, (%) 二甲双胍 磺脲类 55.9 44.1 54.3 55.1 44.9 CITATION Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333-2348. SEE pg 2337 Table (for slide data); pg 2335 “Patients” (for DISCUSSION); pg 2335 “Study design” (for background information) DISCUSSION Inclusion criteria: Study participants were ≥30 years old, and had 3 months prior treatment with either a stable dose of ≥1500 mg/day immediate- or extended-release metformin (MET) or an optimally effective dose of a sulphonylurea (SFU). Patients had an HbA1c ≥7.1% and ≤11.0%, a body mass index (BMI) >25 kg/m2 and <40 kg/m2, and stable body weight (not varying by >10%) for ≥3 months. At baseline, patients in the two treatment sequences were similar in mean age, BMI, fasting serum glucose (FSG), and HbA1c STUDY H8O-MC-GWAO BACKGROUND Randomised, open-label, 2-period crossover noninferiority study of patients with type 2 diabetes previously uncontrolled with MET or an SFU. Exenatide and insulin glargine treatments were administered for 16 weeks each and prestudy dose of MET or SFU was continued. Exenatide was administered twice daily as subcutaneous injection, 60 min before AM and PM meals at 5 µg for first 4 weeks, 10 µg exenatide after 4 weeks. Once-daily insulin glargine treatment was initiated at 10 IU, and was increased weekly by 8, 6, 4, or 2 IU daily if the mean fasting serum glucose (FSG) level on two consecutive days was >10 mmol/L, 7.8 to 10 mmol/L, 6.7 to 7.8 mmol/L, or 5.6 to 6.7 mmol/L, respectively. However, if the mean FSG level was less than 4 mmol/L at any time during the previous week, the insulin glargine dose was not adjusted. Intent-to-treat sample, N=138; mean ± SEM or %. Barnett AH, et al. Clin Ther. 2007;29:2333-2348.

艾塞那肽/甘精胰岛素对比试验: 终点时 HbA1c 变化 甘精胰岛素 (n=127) 艾塞那肽 (n=136) -1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 MET SFU in HbA1c变化 (%) CITATION Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333-2348. SEE pg 2337 1st column 3rd paragraph (for slide data and DISCUSSION) DISCUSSION The reduction in HbA1c was similar in metformin (MET) or sulphonylurea (SFU) patients treated with exenatide (‑1.39 ± 0.12% and ‑1.34 ± 0.13%, respectively) or insulin glargine (‑1.43 ± 0.12% and ‑1.27 ± 0.13%, respectively) STUDY H8O-MC-GWAO BACKGROUND Randomised, open-label, 2-period crossover noninferiority study of patients with type 2 diabetes previously uncontrolled with MET or an SFU. Exenatide and insulin glargine treatments were administered for 16 weeks each and prestudy dose of MET or SFU was continued. Exenatide was administered twice daily as subcutaneous injection, 60 min before AM and PM meals at 5 µg for first 4 weeks, 10 µg exenatide after 4 weeks. Once-daily insulin glargine treatment was initiated at 10 IU, and was increased weekly by 8, 6, 4, or 2 IU daily if the mean fasting serum glucose (FSG) level on two consecutive days was >10 mmol/L, 7.8 to 10 mmol/L, 6.7 to 7.8 mmol/L, or 5.6 to 6.7 mmol/L, respectively. However, if the mean FSG level was less than 4 mmol/L at any time during the previous week, the insulin glargine dose was not adjusted. -1.27 -1.34 -1.39 -1.43 Intent-to-treat sample, N=138; LS mean ± SEM. Barnett AH, et al. Clin Ther. 2007;29:2333-2348.

艾塞那肽/甘精胰岛素对比试验: 终点时 HbA1c 达标患者百分比 5 10 15 20 25 30 35 40 45 艾塞那肽 (n=136) 甘精胰岛素 (n=127) 5 10 15 20 25 30 35 40 45 ≤7.0% HbA1c ≤6.5% HbA1c 患者百分比 40 38 CITATION Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333-2348. SEE pg 2340 Figure 2-C, pg 2337 2nd column 1st paragraph (for slide data and DISCUSSION); pg 2335 “Study design” (for background information) DISCUSSION The percentage of patients achieving HbA1c of ≤7% (exenatide, 38%; insulin glargine, 40%) and ≤6.5% (exenatide 22%; insulin glargine 14%) was similar for both treatments (p=NS for both) STUDY H8O-MC-GWAO BACKGROUND Randomised, open-label, 2-period crossover noninferiority study of patients with type 2 diabetes previously uncontrolled with MET or an SFU. Exenatide and insulin glargine treatments were administered for 16 weeks each and prestudy dose of MET or SFU was continued. Exenatide was administered twice daily as subcutaneous injection, 60 min before AM and PM meals at 5 µg for first 4 weeks, 10 µg exenatide after 4 weeks. Once-daily insulin glargine treatment was initiated at 10 IU, and was increased weekly by 8, 6, 4, or 2 IU daily if the mean fasting serum glucose (FSG) level on two consecutive days was >10 mmol/L, 7.8 to 10 mmol/L, 6.7 to 7.8 mmol/L, or 5.6 to 6.7 mmol/L, respectively. However, if the mean FSG level was less than 4 mmol/L at any time during the previous week, the insulin glargine dose was not adjusted. 22 14 Intent-to-treat sample, N=138 Barnett AH, et al. Clin Ther. 2007;29:2333-2348.

艾塞那肽/甘精胰岛素对比试验: 餐后2小时血糖波动 艾塞那肽/甘精胰岛素对比试验: 餐后2小时血糖波动 甘精胰岛素 (n=127) 艾塞那肽 (n=136) 3.0 2.5 ** 2.0 CITATION Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333-2348. SEE pg 2343 Figure 6 (for slide data); pg 2341 2nd column 2nd paragraph (for DISCUSSION); pg 2335 “Study design” (for background information) DISCUSSION Exenatide treatment led to significantly lower 2-hour postprandial glucose (PPG) excursions compared with insulin glargine in the morning (LS mean difference, mmol/L; -2.2 ± 0.3, p<.001), midday (‑0.5 ± 0.2, p=.016), evening (-2.1 ± 0.3, p<.001) Total daily mean glucose excursion was also significantly lower in exenatide-treated patients compared with insulin glargine-treated patients (‑1.7 ± 0.2, p<.001) STUDY H8O-MC-GWAO BACKGROUND Randomised, open-label, 2-period crossover noninferiority study of patients with type 2 diabetes previously uncontrolled with MET or an SFU. Exenatide and insulin glargine treatments were administered for 16 weeks each and prestudy dose of MET or SFU was continued. Exenatide was administered twice daily as subcutaneous injection, 60 min before AM and PM meals at 5 µg for first 4 weeks, 10 µg exenatide after 4 weeks. Once-daily insulin glargine treatment was initiated at 10 IU, and was increased weekly by 8, 6, 4, or 2 IU daily if the mean fasting serum glucose (FSG) level on two consecutive days was >10 mmol/L, 7.8 to 10 mmol/L, 6.7 to 7.8 mmol/L, or 5.6 to 6.7 mmol/L, respectively. However, if the mean FSG level was less than 4 mmol/L at any time during the previous week, the insulin glargine dose was not adjusted. 1.5 餐后血糖波动 (mmol/L) 1.0 0.5 * * -0.5 早晨 中午 晚上 Intent-to-treat sample, N=138; LS mean ± SEM; *p<.001, exenatide versus insulin glargine; **p=.016, exenatide versus insulin glargine. Barnett AH, et al. Clin Ther. 2007;29:2333-2348.

艾塞那肽/甘精胰岛素对比试验: 治疗期间的体重变化 2 1 体重变化 (kg) - 1 - 2 - 3 2 4 6 8 12 16 18 CITATION Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333-2348. SEE pg 2341 Figure 4 (for slide data) pg 2338 “Change in body weight” and pg 2340 1st column (for DISCUSSION); and pg 2335 “Study design” (for background information) DISCUSSION During exenatide treatment, a mean decrease in body weight of -2.0 ± 0.4 kg occurred in the first period and ‑2.2 ± 0.4 kg during the second period. In contrast, during insulin glargine treatment, mean weight increases of approximately +1.0 ± 0.4 kg (first period) and +2.3 ± 0.4 kg (second period) were observed. Change in body weight from study baseline to endpoint was significantly different between treatments (exenatide, ‑1.6 ± 0.3 kg; insulin glargine, 0.6 ± 0.3; p<.001) STUDY H8O-MC-GWAO BACKGROUND Randomised, open-label, 2-period crossover noninferiority study of patients with type 2 diabetes previously uncontrolled with MET or an SFU. Exenatide and insulin glargine treatments were administered for 16 weeks each and prestudy dose of MET or SFU was continued. Exenatide was administered twice daily as subcutaneous injection, 60 min before AM and PM meals at 5 µg for first 4 weeks, 10 µg exenatide after 4 weeks. Once-daily insulin glargine treatment was initiated at 10 IU, and was increased weekly by 8, 6, 4, or 2 IU daily if the mean fasting serum glucose (FSG) level on two consecutive days was >10 mmol/L, 7.8 to 10 mmol/L, 6.7 to 7.8 mmol/L, or 5.6 to 6.7 mmol/L, respectively. However, if the mean FSG level was less than 4 mmol/L at any time during the previous week, the insulin glargine dose was not adjusted. n=68 体重变化 (kg) - 1 n=70 - 2 - 3 2 4 6 8 12 16 18 20 22 24 28 32 时间 (周) N=138; Intent-to-treat sample, LS mean ± SEM. Barnett AH, et al. Clin Ther. 2007;29:2333-2348.

艾塞那肽/甘精胰岛素对比试验: ≥5% 的患者出现的不良反应† 艾塞那肽/甘精胰岛素对比试验: ≥5% 的患者出现的不良反应† TEAE 甘精胰岛素 N=127 n (%) 艾塞那肽 N=136 恶心 4 (3.1) 58 (42.6) 头痛 12 (9.4) 17 (12.5) 呕吐 13 (9.6) 咳嗽 11 (8.7) 6 (4.4)‡ 感冒 15 (11.8) 11 (8.1)‡ 咽炎 10 (7.9) 4 (2.9)‡ 头晕 7 (5.5)‡ 9 (6.6)‡ CITATION Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333-2348. SEE pg 2341 “Treatment-emergent adverse events” (for slide data); pg 2335 “Study design” (for background information) DISCUSSION The adverse events (number of patients with events) potentially related to study drug reported most frequently by exenatide-treated patients were nausea, headache, and vomiting and by glargine-treated patients were influenza, headache, cough, and pharyngitis More patients reported nausea (43% versus 3%) and vomiting (10% versus 3%) during exenatide treatment compared with glargine treatment Nausea associated with exenatide was generally mild to moderate in nature, and was most common at treatment initiation STUDY H8O-MC-GWAO BACKGROUND Randomised, open-label, 2-period crossover noninferiority study of patients with type 2 diabetes previously uncontrolled with MET or an SFU. Exenatide and insulin glargine treatments were administered for 16 weeks each and prestudy dose of MET or SFU was continued. Exenatide was administered twice daily as subcutaneous injection, 60 min before AM and PM meals at 5 µg for first 4 weeks, 10 µg exenatide after 4 weeks. Once-daily insulin glargine treatment was initiated at 10 IU, and was increased weekly by 8, 6, 4, or 2 IU daily if the mean fasting serum glucose (FSG) level on two consecutive days was >10 mmol/L, 7.8 to 10 mmol/L, 6.7 to 7.8 mmol/L, or 5.6 to 6.7 mmol/L, respectively. However, if the mean FSG level was less than 4 mmol/L at any time during the previous week, the insulin glargine dose was not adjusted. Intent-to-treat sample, N=138; TEAE=treatment-emergent adverse event; †Hypoglycaemic events were analysed separately. Barnett AH, et al. Clin Ther. 2007;29:2333-2348. ‡Data on File, Eli Lilly and Company.

艾塞那肽/甘精胰岛素对比试验: 低血糖发生率 艾塞那肽/甘精胰岛素对比试验: 低血糖发生率 甘精胰岛素 (n=127) 艾塞那肽 (n=136) 40 35 34.5 30 CITATION Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333-2348. SEE pg 2342 “Hypoglycemia” (for slide data); pg 2335 “Study design” (for background information) DISCUSSION Incidence of hypoglycaemia in patients taking adjunctive sulphonylurea (SFU) was not different but was significantly less with exenatide/metformin (MET) compared with glargine/MET Three patients experienced 8 episodes of severe hypoglycaemia during glargine treatment, but no occurrences of severe hypoglycaemia were observed during exenatide treatment STUDY H8O-MC-GWAO BACKGROUND Randomised, open-label, 2-period crossover noninferiority study of patients with type 2 diabetes previously uncontrolled with MET or an SFU. Exenatide and insulin glargine treatments were administered for 16 weeks each and prestudy dose of MET or SFU was continued. Exenatide was administered twice daily as subcutaneous injection, 60 min before AM and PM meals at 5 µg for first 4 weeks, 10 µg exenatide after 4 weeks. Once-daily insulin glargine treatment was initiated at 10 IU, and was increased weekly by 8, 6, 4, or 2 IU daily if the mean fasting serum glucose (FSG) level on two consecutive days was >10 mmol/L, 7.8 to 10 mmol/L, 6.7 to 7.8 mmol/L, or 5.6 to 6.7 mmol/L, respectively. However, if the mean FSG level was less than 4 mmol/L at any time during the previous week, the insulin glargine dose was not adjusted. 30.0 25 25.2 低血糖发生率 (%) 20 15 17.4 14.7 10 * 5 2.6 所有患者 用二甲双胍 治疗的患者 用磺脲类药物 治疗的患者 Intent-to-treat sample, N=138; LS mean (SEM); *p=0.010 Barnett AH, et al. Clin Ther. 2007;29:2333-2348.

艾塞那肽/甘精胰岛素对比试验: 总的低血糖发生比率 艾塞那肽/甘精胰岛素对比试验: 总的低血糖发生比率 艾塞那肽 (n=136) 甘精胰岛素 (n=127) * 所有患者 CITATION Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333-2348. SEE pg 2344 Figure 7-A (for slide data); pg 2335 “Study design” (for background information) DISCUSSION Mean rates of overall hypoglycaemia (episodes/patient-year (95% CI) were significantly less (p<.05) in exenatide-treated patients compared with glargine-treated patients Sulphonylurea (SFU)-treated patients had a similar rates of overall hypoglycaemia. In metformin (MET)-treated patients, exenatide was associated with a lower rate of hypoglycaemia overall compared with glargine (p=0.002). STUDY H8O-MC-GWAO BACKGROUND Randomised, open-label, 2-period crossover noninferiority study of patients with type 2 diabetes previously uncontrolled with MET or an SFU. Exenatide and insulin glargine treatments were administered for 16 weeks each and prestudy dose of MET or SFU was continued. Exenatide was administered twice daily as subcutaneous injection, 60 min before AM and PM meals at 5 µg for first 4 weeks, 10 µg exenatide after 4 weeks. Once-daily insulin glargine treatment was initiated at 10 IU, and was increased weekly by 8, 6, 4, or 2 IU daily if the mean fasting serum glucose (FSG) level on two consecutive days was >10 mmol/L, 7.8 to 10 mmol/L, 6.7 to 7.8 mmol/L, or 5.6 to 6.7 mmol/L, respectively. However, if the mean FSG level was less than 4 mmol/L at any time during the previous week, the insulin glargine dose was not adjusted. 二甲双胍治疗的患者 ** 磺脲类治疗的患者 1 2 3 4 5 6 总的低血糖发生比率 (次/人-年) Intent-to-treat sample, N=138; Incidence densities (number of episodes/exposure) ± 95% CI. *p=.039, exenatide versus insulin glargine; **p<.001, exenatide + metformin versus insulin glargine + metformin. Barnett AH, et al. Clin Ther. 2007;29:2333-2348.

艾塞那肽/甘精胰岛素对比试验: 夜间低血糖发生比率 艾塞那肽/甘精胰岛素对比试验: 夜间低血糖发生比率 艾塞那肽 (n=136) 甘精胰岛素 (n=127) * 所有患者 CITATION Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333-2348. SEE pg 2344 Figure 7-B (for slide data); pg 2335 “Study design” (for background information) DISCUSSION Mean rates of nocturnal hypoglycaemia (episodes/patient-year (95% CI) were significantly less in exenatide-treated patients compared with glargine-treated patients (p<.001) Sulphonylurea (SFU)-treated patients had similar rates of nocturnal hypoglycaemia In metformin (MET)-treated patients, exenatide was associated with a lower rate of nocturnal hypoglycaemia compared with insulin glargine-treated patients (p<.01) STUDY H8O-MC-GWAO BACKGROUND Randomised, open-label, 2-period crossover noninferiority study of patients with type 2 diabetes previously uncontrolled with MET or an SFU. Exenatide and insulin glargine treatments were administered for 16 weeks each and prestudy dose of MET or SFU was continued. Exenatide was administered twice daily as subcutaneous injection, 60 min before AM and PM meals at 5 µg for first 4 weeks, 10 µg exenatide after 4 weeks. Once-daily insulin glargine treatment was initiated at 10 IU, and was increased weekly by 8, 6, 4, or 2 IU daily if the mean fasting serum glucose (FSG) level on two consecutive days was >10 mmol/L, 7.8 to 10 mmol/L, 6.7 to 7.8 mmol/L, or 5.6 to 6.7 mmol/L, respectively. However, if the mean FSG level was less than 4 mmol/L at any time during the previous week, the insulin glargine dose was not adjusted. 二甲双胍治疗的患者 ** 磺脲类治疗的患者 0.5 1 1.5 2 2.5 夜间低血糖发生比率 (次/人-年) Intent-to-treat sample, N=138; Incidence densities (number of episodes/exposure) ± 95% CI . *p<.001, exenatide versus insulin glargine; **p=.002, exenatide + metformin versus insulin glargine + metformin. Barnett AH, et al. Clin Ther. 2007;29:2333-2348.

艾塞那肽对血糖控制的疗效小结 2型糖尿病患者，用艾塞那肽治疗可降低空腹血糖、餐后血糖及HbA1c 无论原先用何种治疗，艾塞那肽均能显著降低血糖 (+ SFU, + MET, + MET + SFU) 从治疗第一天开始，血糖就显著改善（餐后血糖）且血糖改善从30周一直持续到超过3年 (空腹血糖、餐后血糖及 HbA1c) 艾塞那肽在降低HbA1c 方面与甘精胰岛素相同

艾塞那肽治疗伴体重下降 用二甲双胍和/或磺脲类药物治疗的2型糖尿病患者加用艾塞那肽治疗30周： 可降低体重 1.6-2.8 kg 在超过3年的延伸期研究中，艾塞那肽治疗可引起体重进行性下降 平均体重降低 5.3 kg 在与甘精胰岛素及双相门冬胰岛素的对照试验中，艾塞那肽引起体重下降（胰岛素则引起体重增加） 艾塞那肽vs 甘精胰岛素：-2.3 kg vs +1.8 kg DISCUSSION Summarise all points

Summary of Exenatide Safety Data 艾塞那肽最常见的不良反应为轻到中度的胃肠道反应， 在治疗初期最为常见。 艾塞那肽治疗低血糖发生率低 和二甲双胍合用时，艾塞那肽不增加低血糖风险。 和磺脲类药物合用时可能会增加低血糖风险。 通常通过降低磺脲类药物剂量可以避免风险 DISCUSSION Summarise all points 56

内容提要 糖尿病治疗中的困境 肠促胰素效应、激素及以GLP-1为基础的治疗 艾塞那肽临床注册试验及与胰岛素比较试验 ADA/EASD 治疗方案与艾塞那肽

ADA/EASD 关于2型糖尿病的共识声明 第一级: 有很多寻证医学支持的核心治疗 第二级: 寻证医学证据较少的核心治疗 生活方式 + 二甲双胍 + 强化胰岛素 生活方式 + 二甲双胍 + 基础胰岛素 诊断: 生活方式 + 二甲双胍 生活方式 + 二甲双胍 + 磺脲类 第一步 第二步 第三步 第二级: 寻证医学证据较少的核心治疗 生活方式 + 二甲双胍 + 吡格列酮 磺脲类 a 生活方式 + 二甲双胍 + 吡格列酮 (无低血糖 /有水肿(心衰)/ 骨丢失) 生活方式 + 二甲双胍 + GLP-1 受体激动剂 b (无低血糖/可降低体重 /恶心/呕吐 ) 生活方式 + 二甲双胍 + 基础胰岛素 CHF = congestive heart failure Nathan DM, et al. Diabetes Care 2009;32:193-203. 58

艾塞那肽与 ADA/EASD 治疗标准 持续控制HbA1c 能够降低体重 低血糖风险低* 葡萄糖依赖的胰岛素分泌 体重改变 能够降低体重 低血糖风险 低血糖风险低* 胰岛素分泌能力 葡萄糖依赖的胰岛素分泌 心血管风险因子 需要更多对心血管长期保护作用的研究 安全性/耐受性 主要的不良反应为恶心、呕吐、腹泻、抖动、头晕、头痛、消化不良等，恶心主要见于使用早期，多数随时间延长而逐渐消失 使用方便 本品为预充笔，每天两次餐前1小时内注射，无需根据进餐量或运动量调整剂量 HbA1c control Exenatide provides sustained HbA1c control Changes in body weight Treatment with exenatide may have a secondary benefit of weight loss Risk of hypoglycaemia Exenatide is associated with a low risk of hypoglycaemia* Insulin secretory capacity Exenatide results in glucose-dependent insulin secretion CVD risk factors Appropriate long-term studies are needed Safety/Tolerability The most common AEs associated with exenatide are nausea, vomiting, diarrhea, feeling jittery, dizziness, headache, and dyspepsia. Nausea is most common when first starting exenatide, but decreases over time in most patients Ease of use Exenatide comes in a prefilled pen and is injected, twice a day, within 1 hour before meals. No dosage adjustments based on meal size or exercise are required *When exenatide is used with an SFU, there is an increased risk of hypoglycaemia *当艾塞那肽与磺脲类合用时，会增高低血糖风险 59

百泌达® ：起始方便、治疗简单 首次注射后, 百泌达预充笔可在低于25ºC的室温中保存 针头细,创伤小 每支预充笔可使用一个月 每天给药2次，给药时间为2顿主餐前1小时内* 无需根据进餐量或运动量调整剂量 无需额外监测血糖 第一个月5ug每天两次，第二个月开始10ug每天两次 DISCUSSION: BYETTA® can be easily added to a patient’s current therapy Initiate the patient with 5 μg BID; then, based on glycaemic response and tolerability, increase to 10 μg BID after 1 month No dose adjustments are necessary based on meal size or exercise No additional glucose monitoring required BYETTA is available in easy-to-use prefilled pens Before first use, BYETTA must be stored refrigerated at 36ºF to 46ºF (2ºC to 8ºC) After first use, BYETTA can be kept at a room temperature not to exceed 77ºF (25ºC) Do not freeze the BYETTA pen SLIDE BACKGROUND: See accompanying Prescribing Information and safety information included in this presentation * 两餐之间至少间隔6小时 详见相关的使用说明和安全信息 60

百泌达和2型糖尿病治疗 独特的作用机制: GLP-1 受体激动剂 改善 β 细胞功能 卓越的、持久的血糖控制 低血糖发生率低 固定剂量 – 起始方便、治疗简单

Thank you Che Che Ñi

Back up slides

抗艾塞那肽抗体 第30周时，38% 的患者有低滴度的抗艾塞那肽抗体 第30周时，另有6%的患者有较高滴度的抗体 抗体阳性的患者其HbA1c通常与抗体阴性的患者相近 第30周时，另有6%的患者有较高滴度的抗体 在对照研究中约3%的患者其血糖对艾塞那肽的反应有所下降 DISCUSSION In assessing combined results from all 3 AMIGO studies, the glycaemic response to exenatide was sustained in 97% of patients and appeared to be diminished in 3% of patients There were similar rates/types of adverse events between patients who developed anti-exenatide antibodies and those patients who did not BACKGROUND The 3 AMIGO studies were undertaken to evaluate the ability of exenatide to improve glycaemic control in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of metformin (MET), sulphonylurea (SFU), or MET + SFU Three 30-week, placebo-controlled, double-blind, Phase 3 studies were completed in the United States An additional 6% of patients had a high titre antibodies of >1/625 at 30 weeks This slide presents combined data Subjects with type 2 diabetes (currently taking MET, SFU, or MET + SFU) were randomised to placebo (PBO), 5 µg exenatide twice daily (BID), or 10 µg exenatide BID, N = 1446. All subjects also continued current medication. The Last Observation Carried Forward (LOCF) method was applied to the data Treatment-emergent anti-exenatide antibodies were characterised as part of the efficacy and safety profile of exenatide Byetta package insert. San Diego, CA: Amylin Pharmaceuticals, Inc; 2007.

胰腺炎罕见 艾塞那肽 普通人群* 2型糖尿病患者 艾塞那肽使用的患者中有胰腺炎病例的自发报道 至2009年1月31日，使用艾塞那肽的患者中胰腺炎的累计发生率为0.57/1000人年1 普通人群* 最近，对美国普通人群胰腺炎发生率的估计如下: 0.7 /1000 人年2,3,4 其中15‑20% 为重症病例5,6 其中 2-9% 会引起死亡5,6 药物引起的胰腺炎罕见 (仅占所有病例的1.4-2.0% )6 2型糖尿病患者 最近的一项流行病学研究显示2型糖尿病患者胰腺炎的发生率约为非2型糖尿病患者3倍2 Discussion: As of January 31, 2009 the cumulative rate of pancreatitis is 0.57 events per 1000 patient years of exenatide exposure1 Recent estimates of pancreatitis incidence in the general US population are as follows:* 0.7 events per 1000 adults per year2-4 Severe disease develops in 15-20% of those pancreatitis cases5,6 Death occurs in 2-9% of cases5,6 Drug-induced pancreatitis is a relatively rare event (1.4-2.0% of all cases)6 A recent epidemiological study has reported that patients with T2D are at nearly 3 times the risk of developing pancreatitis than those without diabetes2 *Note: The pancreatitis rates in the general population should not be directly compared to those rates seen in exenatide-treated patients. See accompanying Prescribing Information and safety information included in this presentation References: Data on File. 2008, Eli Lilly and Company. Noel R, Braun D, Patterson R, Bloomgren G. Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective, cohort study. [published online ahead of print]. Diabetes Care. doi: dc08-1755v1-0. Steinberg W, Tenner S. Acute Pancreatitis. N Engl J Med. 1994;330:1198-1210. Fagenholz PJ, Fernandez-del Castillo C, Harris NS, et al. Increasing United States hospital admissions for acute pancreatitis, 1988-2003. Ann Epidemiol. 2007;17:491-497. Forsmark CE, Baillie J. AGA Institute technical review on acute pancreatits. Gastroenterology. 2007;132:2022-2044. Frossard JL, Steer ML, Pastor CM. Acute pancreatitis. Lancet. 2008;371:143-152. *注: 不能将普通人群的胰腺炎发生率直接和艾塞那肽治疗的患者相比. 1. Data on File. Eli Lilly and Company, 2008. 2. Noel RA, et al. Diabetes Care. 2009. 3. Steinberg W, Tenner S. N Engl J Med. 1994;3301198-1210. 4. Fagenholz PJ, et al. Ann Epidemiol. 2007;17:491-497. 5. Forsmark CE, Baillie J. Gastroenterology. 2007;132:2022-2044. 6. Frossard JL, et al. Lancet. 2008;371:143-152. 65

内容提要 艾塞那肽和双相门冬胰岛素对比试验

艾塞那肽 10 µg BID + MET plus SFU 艾塞那肽/ 双相门冬胰岛素对比试验 主要假设: 在二甲双胍加磺脲类药物治疗不达标的2型糖尿病患者加用艾塞那肽血糖控制不劣于预混胰岛素 两种治疗疗效差别均数的95%可信区间上限小于0.4%，则认为非劣效 CITATION Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007;50:259-267. SEE pg 260 2nd column 1st paragraph, and pg 261 “Study participants” (for slide data); pg 259 “Aims and hypothesis” and “Materials and methods” (for background information) DISCUSSION The following information will focus on the prospective study that compared the safety and efficacy of exenatide to biphasic insulin aspart 30/70 in patients with type 2 diabetes who failed to achieve adequate glycaemic control when treated with metformin (MET) and a sulphonylurea (SFU) The importance of optimising insulin doses was discussed with investigators both at study initiation and midstudy meetings where they were encouraged to optimise glucose control by titrating insulin doses as high as clinically possible BACKGROUND This 52-week, open-label, noninferiority trial was designed to compare the safety and efficacy of exenatide and premixed insulin Patients failing to reach treatment goals with MET and an SFU were randomised to exenatide (n=253; 5 µg twice daily (BID) 4 weeks, 10 µg thereafter) or premixed insulin (n=248; BID doses titrated for optimal glucose control) The primary endpoint was change in HbA1c at Week 52 筛查 (HbA1c ≥7.0% to ≤11.0%; BMI ≥25 及 ≤40 kg/m2 ) 随机 当前的 MET/SFU 治疗 艾塞那肽 5 µg BID + MET/SFU 艾塞那肽 10 µg BID + MET plus SFU 预混胰岛素 BID + MET 加 SFU (胰岛素治疗目标 FPG <7 mmol/L 及 PPG <10 mmol/L ，每日监测血糖) -2 -1 2 4 8 12 16 28 40 52 时间 (周) Premixed insulin in this study refers to biphasic insulin aspart (30% rapid-acting insulin aspart); Mean dose of premixed insulin increased from 15.7 U/d (week 2) to 24.4 U/d (week 52). Nauck MA, et al. Diabetologia. 2007;50:259-267.

艾塞那肽/ 双相门冬胰岛素对比试验: 患者基线特征 艾塞那肽/ 双相门冬胰岛素对比试验: 患者基线特征 10.0 (6.2) 9.8 (6.3) 糖尿病病程, 年 8.6 (1.1) 8.6 (1.0) HbA1c,% 11.3 (2.8) 11.0 (2.7) 空腹血糖, mmol/L 30.2 (4.2) 30.6 (4.0) BMI, kg/m2 83.4 (15.6) 85.5 (15.7) 体重, kg 49 53 性别, 男性 % 58 (9) 59 (9) 年龄, 岁 预混胰岛素 艾塞那肽 CITATION Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007;50:259-267. SEE pg 263 Table 1 (for slide data); pg 259 “Materials and methods” (for background information) DISCUSSION Baseline characteristics were similar between treatment groups with respect to age, gender, body weight, body mass index (BMI), glycaemic control, and duration of diabetes at baseline Participants were generally overweight with a long history of diabetes and who failed to achieve adequate glycaemic control BACKGROUND This 52-week, open-label, noninferiority trial was designed to compare the safety and efficacy of exenatide and premixed insulin Patients failing to reach treatment goals with metformin (MET) and a sulphonylurea (SFU) were randomised to exenatide (n=253; 5 µg twice daily (BID) 4 weeks, 10 µg thereafter) or premixed insulin (n=248; BID doses titrated for optimal glucose control) The primary endpoint was change in HbA1c at Week 52 ITT sample, mean (SD) shown. Nauck MA, et al. Diabetologia. 2007;50:259-267.

艾塞那肽/ 双相门冬胰岛素对比试验: 终点时 HbA1c 变化 预混胰岛素 * HbA1c变化 (%) 35 32% 30 0.0 24% CITATION Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007;50:259-267. SEE pg 259 2nd column 1st paragraph, pg 263 1st column 2nd paragraph, and pg 264 Table 2 (for slide data and DISCUSSION); pg 259 “Methods” (for background information) DISCUSSION Analysis of all patients who entered the study and were randomised to a treatment group (the intent-to-treat [ITT] population) showed that the HbA1c change at endpoint was nonsignificant (95% CI: -0.32 to 0.01) between exenatide and premixed insulin treatments (figure on left). This demonstrates that the primary efficacy conclusion was consistent between the ITT population and the subset of patients that complied with the study protocol. A significantly greater (p=.038) proportion of exenatide-treated patients in the ITT dataset achieved a target HbA1c of ≤7% at endpoint compared to patients treated with premixed insulin (figure on right) BACKGROUND This 52-week, open-label, noninferiority trial was designed to compare the safety and efficacy of exenatide and premixed insulin Patients failing to reach treatment goals with metformin (MET) and a sulphonylurea (SFU) were randomised to exenatide (n=253; 5 µg twice daily (BID) 4 weeks, 10 µg thereafter) or premixed insulin (n=248; BID doses titrated for optimal glucose control) The primary endpoint was change in HbA1c at Week 52 25 -0.5 20 治疗达标患者 (%) -1.0 15 -0.89% -1.04% 10 -1.5 5 -2.0 -0.15% (95% CI, -0.32 to 0.01, p=.067) HbA1c ≤7% ITT sample; left panel; ITT sample, mean change ± SE shown; NSD=nonsignificant differences; Right panel: between-group difference *p=.038 Nauck MA, et al. Diabetologia. 2007;50:259-267.

艾塞那肽/ 双相门冬胰岛素对比试验: 7点自我血糖监测谱 艾塞那肽/ 双相门冬胰岛素对比试验: 7点自我血糖监测谱 艾塞那肽, 0周 预混胰岛素, 0周 艾塞那肽, 52周 预混胰岛素, 52周 13 13 12 12 11 11 CITATION Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007;50:259-267. SEE pg 264 Figure 3 (for slide data); pg 259 “Materials and Methods” and pg 263 “Glycaemic Control” (for background information) DISCUSSION At postbreakfast and postsupper, patients treated with exenatide achieved significantly better glycaemic control compared to patients treated with premixed insulin At prebreakfast, prelunch, and 03:00 hours, patients treated with premixed insulin achieved significantly better glycaemic control compared to patients treated with exenatide Self-monitored blood glucose (SMBG) profiles indicated significantly reduced endpoint glucose levels at all time points in both treatment groups (compared to within-group baseline) BACKGROUND This 52-week, open-label, noninferiority trial was designed to compare the safety and efficacy of exenatide and premixed insulin Patients failing to reach treatment goals with metformin (MET) and a sulphonylurea (SFU) were randomised to exenatide (n=253; 5 µg twice daily (BID) 4 weeks, 10 µg thereafter) or premixed insulin (n=248; BID doses titrated for optimal glucose control) The primary endpoint was change in HbA1c at Week 52 血糖 (mmol/L) 10 10 9 9 † 8 * 8 * ** 7 7 ‡ 03:00 03:00 晚餐前 午餐后 午餐前 晚餐前 午餐后 晚餐前 早餐前 午餐后 早餐前 早餐后 早餐后 午餐后 ITT sample, mean (SE) shown; significantly lower mean glucose level observed for exenatide *p<.001, premixed insulin **p=.0370; †p=.0040; ‡p=.002. Nauck MA, et al. Diabetologia. 2007;50:259-267. Copyright © 2007 Springer-Verlag. Reprinted with permission from Springer-Verlag.

艾塞那肽/ 双相门冬胰岛素对比试验: 体重变化 艾塞那肽/ 双相门冬胰岛素对比试验: 体重变化 艾塞那肽 预混胰岛素 3 +2.9 kg 2 1 CITATION Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007;50:259-267. SEE pg 263 Figure 2-B and 2nd column 2nd paragraph and pg 264 Table 2 (for slide data); pg 259 “Materials and methods” (for background information) DISCUSSION A statistically significant between-group difference in body weight, with exenatide treatment group showing a decrease in body weight, was observed as early as Week 2 of the study and progressed to a difference of over 5 kg at Week 52 No diet or exercise regimens were provided in the study BACKGROUND This 52-week, open-label, noninferiority trial was designed to compare the safety and efficacy of exenatide and premixed insulin Patients failing to reach treatment goals with metformin (MET) and a sulphonylurea (SFU) were randomised to exenatide (n=253; 5 µg twice daily (BID) 4 weeks, 10 µg thereafter) or premixed insulin (n=248; BID doses titrated for optimal glucose control) The primary endpoint was change in HbA1c at Week 52 5.4 kg 体重变化 (kg) -1 * * * -2.5 kg -2 * * * * -3 * 2 4 8 12 16 28 40 52 时间 (周) ITT sample, mean (SE) shown. p<.001, exenatide versus premixed insulin at postbaseline time points. Nauck MA, et al. Diabetologia. 2007;50:259-267. Copyright © 2007 Springer-Verlag. Reprinted with permission from Springer-Verlag.

艾塞那肽和胰岛素对比试验小结 艾塞那肽和双相门冬胰岛素相比: 血糖改善程度相似 艾塞那肽引起体重下降 预混胰岛素伴随体重增加 空腹血糖控制相似 艾塞那肽能更好地控制餐后血糖，艾塞那肽治疗组有更多的患者 HbA1c ≤7.0% DISCUSSION Summarise all points